PROJECT ABSTRACT Prostate-related urinary symptoms, including weak stream and increased frequency of urination especially at night, affect most men of advancing age and command billions of dollars annually. Although benign prostatic enlargement was originally thought to be the only risk factor, new evidence suggests additional mechanisms may contribute. Exposure to the persistent environmental contaminant 2,3,7,8 tetrachlorobenzo-p-dioxin (TCDD), during development (in utero) and via lactation, thickens prostatic smooth muscle in monkeys and mice and exacerbates urinary dysfunction in a mouse model of benign prostatic hyperplasia. TCDD-mediated prostatic smooth muscle thickening is likely important because smooth muscle dysfunction is proposed as a major mechanism of prostate-mediated voiding dysfunction in men and is a key target for current therapeutics. The proposed studies test the hypothesis that in utero and lactational TCDD exposure causes smooth muscle and voiding dysfunction by a mechanism involving impaired prostatic neuroanatomical development. These studies are innovative because they use a novel axon quantification method to evaluate the impact of TCDD on noradrenergic axon density, deploy fluorescent encoded calcium sensors in prostate smooth muscle to quantify the impact of TCDD on nerve-evoked smooth muscle contraction, and leverage contrast-enhanced ultrasound to test whether TCDD impedes the passage of urine through the urethra. The proposed studies will develop the candidate's career by building technical competency in toxicology, neuroscience, and physiology, assay design, and collaborative science while also developing skills in business, leadership, and networking.